Carotenoids exist extensively in the nature and current commercial carotenoid products mainly include beta-carotene, astaxanthin, lycopene, canthaxanthin and lutein, etc. which are widely used in the food, cosmetics, fodder, pharmaceutical industries and other fields as nutrient supplements and colorants. Carotenoids are insoluble in water, rarely soluble in oil, quite sensitive to light, heat and oxygen and cannot be directly used. Generally, carotenoids shall be refined and made into different preparation forms before application in pharmaceutical, health care product, food and fodder fields, since carotenoid preparations can significantly improve bioavailability, pigmentation effect and reduce the dosage.
Reports on preparation methods of carotenoids mainly include the following methods:
WO91/06292 and WO94/19411 introduce a method for preparing water-dispersible carotenoid powders by grinding beta-carotene into 2˜10 μm particles with a colloid mill and then drying.
U.S. Pat. No. 3,998,753 records a method for preparing water-dispersible carotenoids with a particle size of less than 1 μm. In such method, carotenoids and other additives are first made into an organic solvent solution, and then added into a water solution containing gelatin, disperser and stabilizer to form emulsion after high-speed shearing; the organic solvent is removed, spray drying and then the required product can be obtained.
According to the method for preparing water-dispersible carotenoid powders in EP0065193, carotenoids are dissolved in a volatile water-mixable solvent within 10 seconds under 50˜200° C. and then quickly mixed with water solution containing protective colloid under 0˜50° C., wherein carotenoids are dispersed in the protective colloid in the size of less than 0.5 μm and carotenoid powders can be obtained after removing the solvent and drying. In CN102361561A, an instant stable suspension for some amorphous carotenoid particles is obtained with similar technology.
CN102281859A discloses a method for preparing an emulsion composition mainly by mixing an oil phase containing carotenoids with an aqueous phase containing various emulsifiers; in CN101312655B, products are also obtained with similar technology through spray drying of emulsion.
CN1233169A reports two supercritical fluid treatment technologies: in technology A, carotenoids are first dissolved in supercritical dimethyl ether under high temperature and high pressure, and then rapidly decompressed to obtain powder-like carotenoid particles; in technology B, carotenoids are first dissolved in subcritical or supercritical compressed gas under high temperature and high pressure, then such solution is dispersed in other ingredients, and then the compressed gas was removed in such mixture to obtain powder-like preparations.
U.S. Pat. No. 6,056,791 also reports a technology, in which carotenoids and a supercritical fluid are mixed under a certain pressure until a solution containing 5%-90% supercritical fluid is formed. Melting point of the selected supercritical fluid shall be at least 40° C. lower than that of the carotenoid. Then, the temperature is adjusted to 50° C. higher or lower than the melting point of the supercritical fluid and the pressure is reduced to atmospheric pressure. Under such conditions, the supercritical fluid will be gasified quickly and the particle size of carotenoid can reach 0.7 μm-5 μm.
DE2943267 mentions a method for preparing solid drugs by dissolving beta-carotene in a supercritical fluid, quickly decompressing to obtain beta-carotene in fine particle and then adding other ingredients.
The Applicant has also successively applied for a series of patents, including a method for preparing water-dispersible carotenoid powder (Patent Publication No.: CN1836652A) applied in 2005, a method for preparing high all-trans beta-carotene (Patent Publication No.: CN101016259A) applied in 2007, a method for preparing a nano-dispersed high all-trans carotenoid microcapsule (Patent Publication No.: CN101549273B) applied in 2009 and a method for preparing an isomer ratio controllable carotenoid microcapsule (Patent Publication No.: CN101879428A) applied in 2010.
The aforesaid forms are all emulsion, microcapsule and other water-dispersible or solid dosage forms and are difficult to be applied in oil phase system. Reports on preparation methods of dosage forms applied in oil phase system mainly are:
CN102341002A relates to obtaining 0.01˜10 g/kg carotenoid vegetable oil solution with maximum concentration of only 1% by processing carotenoid oil suspension through changing the heating technology, wherein carotenoid has very poor chemical stability in oil solution with likely side reactions.
CN1185433 reports a liquid-oil-mixable carotenoid preparation, wherein carotenoid water-dispersible phase is added into oil phase to make W/O emulsion, in which the aqueous phase liquid drop size approaches to 1 μm and carotenoid particle size reaches to 0.1˜0.2 μm. However, due to a large content of solvent, emulsifier and excipients, the maximum content of carotenoid is only around 1% and the complicated emulsion system has a poor stability in application and is unable to adapt to high temperature, high pressure and other severe processing conditions.
In CN101611876, carotenoids and soybean phospholipids are first grinded into an emulsion particle solution and then mixed with vegetable oil for dilution and smashing to obtain particle emulsion, wherein the carotenoid particle size is only 5˜10 μm;
Currently, the general carotenoid oil suspension fluid is obtained by directly mixing and grinding carotenoid crystals with vegetable oil. In recent years, improvements are made on such basis in related patents. In CN101828693A, carotenoid oil suspension fluid with particle size of around 10 μm is obtained by processing carotenoid crystals with tetrahydrofuran, ethanol and vegetable oil, etc; in CN102552173A, carotenoid oil suspension fluid with average particle size of less than 5 μm is obtained by putting carotenoid solution into vegetable oil via atomization. However, the uniformity and carotenoid particle size in these 2 technologies cannot reach the emulsion level.
In conclusion, the water-dispersible form of carotenoid can generally reach a smaller particle size and have good stability in the form of microcapsule; while the oil-dispersible form mostly has a larger particle size and the effective substance is directly exposed to dispersion medium with poor stability, wherein a smaller particle size can be realized in only a few methods and the maximum content is only around 1% due to formula restrictions with no dense protective layer on carotenoids.